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專任教師

蔡錦華 教授兼主任(所長)

聯絡電話:02-2312-3456 轉 88289, 88298

E-mail: chtsai@ntu.edu.tw

個人資料

專長:

EB 病毒之分子生物學

學歷:

台灣大學微生物所教授 (2002/08~)
台灣大學微生物所副教授 (1992/08-2002/07)
美國耶魯大學藥學系博士後研究 (1983/07-1984/08)

經歷:

美國俄亥俄州立大學微生物及免疫學所

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目前進行研究

Epstein-Barr virus (EBV) is the first defined human oncogenic virus. It mainly infects lymphoid and epithelial cells. In vivo, EBV is highly associated with many human malignancies of these two cell types, such as Burkitt’s lymphoma (BL), NK/T cell lymphoma, Hodgkin’s lymphoma, post-transplant lymphoproliferative diseases (PTLD), nasopharyngeal carcinoma (NPC), and gastric carcinoma. The latter two are so called “lymphoepithelioma”-like carcinomas, which are characterized by the heavy infiltration of nonmalignant lymphocytes. Differentially from other human carcinomas, these two lymphoepitheliomas have rarely mutated or abnormally expression of well-known oncogenes or tumor suppressor genes, suggesting that development of these cancers may have an unusual cellular background. In vitro, EBV infection converts primary human B cells into unlimitedly proliferating lymphoblastoid cell lines (LCLs). Unlike other human oncogenic viruses, which disrupt the cell cycle regulation by interacting with pRB and p53-dependent checkpoints, how EBV breaks the tightly-regulated cell cycle and maintains the cells in proliferative status have not been well understood.

To understand the pathogenic mechanisms involved in EBV-associated malignancies, four major long-term goals are proposed in our lab: (1) to set up an EBV-immortalized human B cell model and establishment of an in vitro B cell-epithelial co-culture model to mimic the in vivo microenvironment in nasopharyngeal area, which is probably the first EBV infection site in human body. (2) identification and characterization of cellular and viral factors that are unusually expressed in EBV-associated diseases (3) elucidation of potencies of these molecules as clinical diagnosis and prognosis for EBV-associated diseases (4) establishment of a drug-screening system for EBV-associated diseases by in vitro cell infection system.

Hypothesis Model 1

Hypothesis Model 2

In vitro, EBV can immortalize primary B cells into unlimited proliferative LCL, which is different from the temporary B cell proliferation induced by other B cell stimuli, such as treatment with IL4/CD40, LPS and polyI:C. According to our and others’ study, we hypothesize there are three stages for EBV immortalization. Firstly, EBV envelope protein gp350 and gp42 binds to its CR2 receptor and MHC class II antigen co-receptor on B cells; this binding action activates B cells but not promotes B cell proliferation. Some data from UV-irradiated EBV infected B cells support this theory. Secondly, EBV enters the B cells and triggers some signaling pathways which promote infected cells proliferation. So far, these B cell reactions can also be triggered by classical B cell activators, such as CD40 plus IL4, LPS, or polyI:C. B cells are proliferated temporarily under the circumstances. Anyway, B cells are died within days or weeks in CD40/IL4, LPS or polyI:C treatment. Finally, EBV maintains the infected B cells proliferation and immortalizes them into LCL. Comparing to primary B cells, EBV infected B cells display dramatically changes in expression of phosphatase, some CD markers, protein tyrosine kinase. We hypothesize that microenvironment created by EBV infection may determine cell fate of B cell and also switch EBV life cycle status. Our multifaceted approaches will reveal and dissect the molecular mechanisms between EBV immortalization and B cell activation.

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研究室成員

博士班研究生:陳奐勻
碩士班研究生:楊宜瑾

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研究成果

蔡錦華教授 (corresponding author*)
1. Wang YP, Lin CF, Tsai SC, Tsai CH, Yeh TH. Upregulation of Caveolin-1 correlate with Akt expression and poor prognosis in NPC patients. Laryngoscope. 2015 Jul;125(7):E231-8.
2. Lin SJ†, Wu SW, † Chou YC, Lin JH, Huang YC, Chen MR如), Ma N*, Tsai CH.* Novel expression and regulation of TIMP-1 in Epstein Barr virus-infected cells and its impact on cell survival. Virology. 2015 Jul;481:24-33. (†, equal contribution)
3. Lai KY†, Chou YC†, Lin JH†, Liu Y, Lin KM, Doong SL, Chen MR, Yeh TH, Lin SJ,* Tsai CH.* Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cδ Pathway. J Virol. 2015 Jun 1;89(11):5968-80. (†, equal contribution)
4. Lin JH, Lin JY, Chou YC, Chen MR, Yeh TH, Lin CW, Lin SJ,* Tsai CH.* Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1. Blood. 2015 Apr 2;125(14):2228-38.
5. Chang CW, Lee CP, Su MT, Tsai CH, Chen MR.* BGLF4 kinase modulates the structure and transport preference of the nuclear pore complex to facilitate nuclear import of Epstein-Barr virus lytic proteins. J Virol. 2015 Feb;89(3):1703-18.
6. Fang CY, Wu CC, Hsu HY, Chuang HY, Huang SY, Tsai CH, Chang Y, Tsao GS, Chen CL, Chen JY.* EGCG inhibits proliferation, invasiveness and tumor growth by up-regulation of adhesion molecules, suppression of gelatinases activity, and induction of apoptosis in nasopharyngeal carcinoma cells. Int J Mol Sci. 2015 Jan 23;16(2):2530-58.
7. Lin SJ*, Lo M, Kuo RL, Shih SR, Ojcius DM, Lu J, Lee CK, Chen HC, Lin MY, Leu CM, Lin CN, Tsai CH.* The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection. J Biomed Sci. 2014 Nov 18;21:99.
8. Su MT, Liu IH, Wu CW, Chang SM, Tsai CH, Yang PW, Chuang YC, Lee CP, Chen MR.* Uracil DNA glycosylase BKRF3 contributes to Epstein-Barr virus DNA replication through physical interactions with proteins in viral DNA replication complex. J Virol. 2014 Aug;88(16):8883-99.
9. Chiu SH, Wu MC*, Wu CC, Chen YC, Lin SF, Hsu JT, Yang CS, Tsai CH, Takada K, Chen MR, Chen JY.* Epstein-Barr virus BALF3 has nuclease activity and mediates mature virion production during the lytic cycle. J Virol. 2014 May;88(9):4962-75.
10.Huang SY, Fang CY, Wu CC, Tsai CH, Lin SF, Chen JY*. Reactive oxygen species mediate epstein-barr virus reactivation by N-methyl-n'-nitro-N-nitrosoguanidine. PLoS One. 2013 Dec 20;8(12):e84919.
11.Tsai SC, Lin SJ, Lin CJ, Chou YC, Lin JH, Yeh TH, Chen MR, Huang LM, Lu MY, Huang YC, Chen HY, Tsai CH.* Autocrine CCL3 and CCL4 induced by the oncoprotein LMP1 promote Epstein-Barr virus-triggered B cell proliferation. J Virol. 2013 Aug;87(16):9041-52.
12.Chou YC, Chen CL, Yeh TH, Lin SJ, Chen MR, Doong SL, Lu J, Tsai CH.* Involvement of recepteur d'origine nantais receptor tyrosine kinase in Epstein-Barr virus-associated nasopharyngeal carcinoma and Its metastasis. Am J Pathol. 2012 Nov;181(5):1773-81.
13.Chang LS, Wang JT, Doong SL, Lee CP, Chang CW, Tsai CH, Yeh SW, Hsieh CY, Chen MR.* Epstein-Barr virus BGLF4 kinase downregulates NF-κB transactivation through phosphorylation of coactivator UXT. J Virol. 2012 Nov;86(22):12176-86.
14.Jou SY, Chang CC, Wu CH, Chen MR, Tsai CH, Chuang WH, Chen YH, Cheng AL, Doong SL.* BCL10GFP fusion protein as a substrate for analysis of determinants required for Mucosa-Associated Lymphoid Tissue 1 (MALT1)-mediated cleavage. J Biomed Sci. 2012 Oct 5;19(1):85.
15.Fang CY, Huang SY, Wu CC, Hsu HY, Chou SP, Tsai CH, Chang Y, Takada K, Chen JY* The synergistic effect of chemical carcinogens enhances epstein-barr virus reactivation and tumor progression of nasopharyngeal carcinoma cells. PLoS One. 2012 Sep;7(9):e44810.
16.Lee CP†, Liu PT†, Kung HN, Su MT, Chua HH, Chang YH, Chang CW, Tsai CH, Liu FT, Chen MR.* The ESCRT machinery is recruited by the viral BFRF1 protein to the nucleus-associated membrane for the maturation of Epstein-Barr Virus. PLoS Pathog. 2012 Sep;8(9):e1002904. (†, equal contribution)
17.Chua HH, Chiu HY, Lin SJ, Weng PL, Lin JH, Wu SW, Tsai SC, Tsai CH.* p53 and Sp1 cooperate to regulate the expression of Epstein-Barr viral Zta protein. J Med Virol. 2012 Aug;84(8):1279-88.
18.Chang YH, Lee CP, Su MT, Wang JT, Chen JY, Lin SF, Tsai CH, Hsieh MJ, Takada K, Chen MR.* Epstein-Barr virus BGLF4 kinase retards cellular S-phase progression and induces chromosomal abnormality. PLoS One. 2012 Jun;7(6):e39217.
19.Huang SY, Hsieh MJ, Chen CY, Chen YJ, Chen JY, Chen MR, Tsai CH, Lin SF*, Hsu TY* Epstein-Barr virus Rta-mediated transactivation of p21 and 14-3-3σ arrests cells at the G1/S transition by reducing cyclin E/CDK2 activity. J Gen Virol. 2012 Jan;93(Pt 1):139-49.
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